Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice
Open accessAbstract
Fragile X syndrome (FXS), the most commonly inherited form of mental retardation and autism, is caused by transcriptional silencing of the fragile X mental retardation 1 (FMR1 ) gene and consequent loss of the fragile X mental retardation protein. Despite growing evidence suggesting a role of specific receptors and biochemical pathways in FXS pathogenesis, an effective therapeutic method has not been developed. Here, we report that abnormalities in FMR1 knockout (KO) mice, an animal model of FXS, are ameliorated, at least partially, at both cellular and behavioral levels, by an inhibition of the catalytic activity of p21-activated kinase (PAK), a kinase known to play a critical role in actin polymerization and dendritic spine morphogenesis. Greater spine density and elongated spines in the cortex, morphological synaptic abnormalities commonly observed in FXS, are at least partially restored by postnatal expression of a dominant negative (dn) PAK transgene in the forebrain. Likewise, the deficit in cortical long-term potentiation observed in FMR1 KO mice is fully restored by the dnPAK transgene. Several behavioral abnormalities associated with FMR1 KO mice, including those in locomotor activity, stereotypy, anxiety, and trace fear conditioning are also ameliorated, partially or fully, by the dnPAK transgene. Finally, we demonstrate a direct interaction between PAK and fragile X mental retardation protein in vitro . Overall, our results demonstrate the genetic rescue of phenotypes in a FXS mouse model and suggest that the PAK signaling pathway, including the catalytic activity of PAK, is a novel intervention site for development of an FXS and autism therapy.
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Core FXS mouse deficits, including protein synthesis, dendritic spine density and morphology, long-term depression, and audiogenic seizures, are consistently rescued by more than ten genetic approaches and multiple drug classes.
“One striking conclusion of the broad array of preclinical studies is that these core deficits can be consistently rescued by more than ten genetic approaches and multiple classes of pharmacological compounds including mGluR antagonists (MPEP, fenobam, mavoglurant and CTEP), GABA agonists, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), mechanistic target of rapamycin (mTOR) inhib”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [55]
Expression of a dominant-negative PAK mutant in the forebrain of Fmr1 knockout mice improved behavioral abnormalities such as impaired locomotor activity, stereotypical anxiety, and trace fear conditioning, suggesting PAK signaling is a therapeutic target.
“Expression of a dominant-negative mutant of PAK in the forebrain of Fmr1 KO mice led to an improvement of several behavioral abnormalities, such as impaired locomotor activity, stereotypical anxiety, and trace fear conditioning, suggesting that the PAK signaling pathway could also represent a bona fide site for therapeutic intervention (93).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [93]
Experimental interventions rescue subsets of behavioral abnormalities in mouse models of autism.
“Experimental interventions, working through diverse genetic and pharmacological mechanisms, rescue subsets of behavioral abnormalities in these mouse models (31, 43, 48–52).”
From Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism (2012) · cites this paper as [48]
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- Authors
- Hayashi, M. L., Rao, B. S. S., Seo, J.-S., Choi, H.-S., Dolan, B. M., Choi, S.-Y., Chattarji, S., & Tonegawa, S.
- Affiliations
- Howard Hughes Medical Institute (US)
- National Institute of Mental Health and Neurosciences (IN)
- Department of Physiology, College of Dentistry, Seoul National University, Seoul 110-749 Korea; and
- Seoul National University (KR)
- Tata Institute of Fundamental Research (IN)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-07-03
- Volume
- 104
- Issue
- 27
- Pages
- 11489-11494
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1899186
- OpenAlex
- W2029950812
- Cited by
- 281
- References
- 43
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 7 · 2022: 7 · 2021: 10 · 2020: 8 · 2019: 11 · 2018: 14 · 2017: 14 · 2016: 16 · 2015: 12 · 2014: 19 · 2013: 25 · 2012: 27
- FWCI
- 13.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- Wellcome Trust
- National Institute of Mental Health (R01-MH78821, PH50 MH58880, P50MH058880, R01MH078821)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- fragile X syndrome, p21-activated kinase, Fmr1 knockout mice, FMRP, dendritic spine morphology, long-term potentiation, synaptic plasticity, actin polymerization, autism spectrum disorder
- MeSH terms
- Animals, Behavior, Animal, Disease Models, Animal, Fragile X Syndrome, Male, Mice, Inbred C57BL, Mice, Transgenic, Protein Serine-Threonine Kinases, Mice, Knockout, Dendritic Spines, Mice, p21-Activated Kinases
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